Process and means for the eradication of ticks in the habitats of small mammals

ABSTRACT

Disclosed is a process for using a compound according to formula (I) or formula (II) to prepare a mixture for the eradication of ticks in the living quarters of small mammals, especially cats and dogs. Said process consists in applying as needed to the animal or animals of the habitat concerned a topical formulation in sufficiently pesticidal quantities of a compound according to formula (I), or possibly formula (II), at monthly intervals.

[0001] The present invention relates to a procedure for the eradicationof parasites, namely parasites of the order of Siphonaptera, especiallyfleas, such as, for example, Ctenocephalides felis and canis, butlike-wise the other fleas of small mammals such as, for example, rabbitsor laboratory animals.

[0002] The control of parasites of small domestic mammals, for exampledogs and cats, and especially of fleas, is known to be extremelydifficult.

[0003] Generally, it is attempted to control the animals themselves,either with the aid of flea collars containing various insecticides, orby topical application of preparations based on insecticides.

[0004] Nevertheless, the fleas always remain present in the environmentof the animal, and especially in the premises of pets, such as domesticpremises, kennels or catteries, as well as laboratories keeping animals.

[0005] The eradication of fleas in these premises with the aid ofpesticides or agents for chemical treatment or the premises is adifficult operation and, except for permanently leaving the premisescovered in an insecticidal substance, which can, in the long term, havean undoubted toxicity, reinfestation takes place rapidly.

[0006] Thus it only remains to regularly treat the animals with the aidof insecticides having a period of efficacy which is as great aspossible, in order to reduce the periodicity and the cost of thetreatments.

[0007] Thus the use has recently been proposed, for the treatment offleas and of ticks in small animals, of topical preparations in the formof preparations for spraying or of concentrated preparations for pointcutaneous application (spot on) whose active principle is formed by1-[2,6-Cl₂-4-CF₃-phenyl]-3-CN-4-[SO-CF₃]-5-NH₂-pyrazole, whosenon-proprietary name is fipronil.

[0008] In fact, the compounds belonging to the pyrazole, especiallyphenylpyrazole, families described in the Patents EP-A-295 217 andEP-A-352 944 have turned out to be extremely efficacious against fleas.

[0009] The period of anti-flea efficacy of fipronil, in the form of aconcentrated solution for point application, called a spot on solution,can exceed 2 to 3 months in dogs and six weeks in cats.

[0010] In view of these performances, the users are naturally tempted toprolong the periods between two applications so as to benefit from thiseffect of long duration.

[0011] A possible explanation for the long duration of activity on theanimal can be connected to the observation that fipronil dissolves inthe sebum and the sweat glands to be released over a long time.

[0012] In a communication (Meo N. J. et al.; Proc. Am. Assoc. Vet.Parasitol (41 Meet., 52, 1996)), it was stated that there was aconsiderable increase in the percentage of non-reappearance of fleas innon-treated premises if the animals frequenting these premises (cats,dogs) received monthly administrations of sprays of the productFrontline® Spray containing fipronil.

[0013] The present invention proposes to simplify and to further improvethis flea control.

[0014] A subject of the invention is thus a procedure for eradication offleas in domestic or accommodation premises of mammals of small size,especially cats and dogs, characterized in that a concentrated topicalpreparation for point application, of the spot-on type in anefficaciously parasiticidal quantity of a compound of formula I or,optionally, of formula II is applied periodically to the animal or theanimals of the premises considered, according to a monthly periodicity.

[0015] The formula I is the following formula:

[0016] in which:

[0017] R₁ is CN or methyl or a halogen atom;

[0018] R₂ is S(O)_(n)R₃ or 4,5-dicyanoimidazol-2-yl or haloalkyl;

[0019] R₃ is alkyl or haloalkyl;

[0020] R₄ is a hydrogen or halogen atom; or an NR₅R₆, S(O)_(m)R₇,C(O)—R₇, C(O)O—R₇, alkyl, haloalkyl or OR₈ radical or an —N═C (R₉) (R₁₀)radical;

[0021] R₅ and R₆ independently are the hydrogen atom or an alkyl,haloalkyl, C(O)alkyl, alkoxycarbonyl or S(O)_(r)CF₃ radical; or R₅ andR₆ can together form a divalent alkylene radical which can beinterrupted by one or two divalent heteroatoms, such as oxygen orsulphur;

[0022] R₇ is an alkyl or haloalkyl radical;

[0023] R₈ is an alkyl or haloalkyl radical or a hydrogen atom;

[0024] R₉ is an alkyl radical or a hydrogen atom;

[0025] R₁₀ is a phenyl or heteroalkyl group which is optionallysubstituted by one or more halogen atoms or groups such as OH, —O-alkyl,—S-alkyl, cyano or alkyl;

[0026] R₁₁ and R₁₂ are, independently of one another, a hydrogen orhalogen atom, or optionally CN or NO₂;

[0027] R₁₃ is a halogen atom or a haloalkyl, haloalkoxy, S(O)_(q)CF₃ orSF₅ group;

[0028] m, n, q and r are, independently of one another, an integer equalto 0, 1 or 2;

[0029] X is a trivalent nitrogen atom or a C—R₁₂ radical, the threeother valencies of the carbon atom being part of the aromatic ring;

[0030] with the reservation that when R₁ is methyl, R₃ is haloalkyl, R₄is NH₂, R₁₁ is Cl, R₁₃ is CF₃ and X is N; or when R₂ is4,8-dicyanoimidazol-2-yl, R₄ is Cl, R₁₁ is Cl, R₁₃ is CF₃ and X is═C—Cl.

[0031] The formula II is the following formula:

[0032] where Y is hydrogen or halogen

[0033] R₁₄ is hydrogen or methyl

[0034] and Z is —(CH₂)_(n)— with n=1 or 2.

[0035] Preferably, in the formula (I),

[0036] R₁ is CN or methyl;

[0037] R₂ is S(O)_(n)R₃;

[0038] R₃ is haloalkyl or ethyl

[0039] R₄ is a hydrogen or halogen atom; or an NR₅R₆, S(O)_(m)R₇,C(O)R₇, alkyl, haloalkyl or OR₈ radical or an —N═C(R₉) (R₁₀) radical;

[0040] R₅ and R₆ independently are the hydrogen atom or an alkyl,haloalkyl, C(O)alkyl, S(O)_(r)CF₃ radical; or R₅ and R₆ can togetherform a divalent alkylene radical which can be interrupted by one or twodivalent heteroatoms, such as oxygen or sulphur;

[0041] R₁₁ and R₁₂ are, independently of one another, a hydrogen orhalogen atom;

[0042] with the reservation that when R₁ is methyl, R₃ is haloalkyl, R₁is NH₂, R₁₁ is Cl, R₁₃ is CF₃ and X is N.

[0043] Compounds of formula (I) which will be considered are veryparticularly those in which R₁ is CN. Compounds will also be consideredin which R₁₃ is haloalkyl, preferably CF₃, or R₂ is S(O)_(n)R₃ with R₃being haloalkyl or X═C—R₁₂, R₁₂ being a halogen atom. It is alsopreferred that R₁₁ is a halogen atom.

[0044] A preferred class of compounds of formula (I) is formed by thecompounds where R₁ is CN, R₃ is haloalkyl, R₄ is NH₂, R₁₁ and R₁₂ areindependently of one another a halogen atom, and/or R₁₃ is haloalkyl.

[0045] The alkyl radicals of the definition of the compounds of formulae(I) generally comprise from 1 to 6 carbon atoms. The ring formed by thedivalent alkylene radical representing R₅ and R₆ as well as the nitrogenatom to which R₅ and R₆ are attached is generally a ring with 5, 6 or 7members.

[0046] A compound of formula (I) which is very particularly preferred inthe invention is

[0047] 1-[2,6-Cl₂-4-CF₃-phenyl]-3-CN-4-[SO—CF₃]-5-NH₂-pyrazole, calledfipronil below.

[0048] Among numerous other advantageous compounds, it is possible tomention 1-[2,6-Cl₂-4-CF₃-phenyl]-3-CN-4-[SO—C₂H₅]-5-NH₂-pyrazole.

[0049] The compounds of formula (I) can be prepared according to one orother of the processes described in the Patent ApplicationsWO-A-87/3781, 93/6089, 94/21606 or European EP-A-0 295 117, or any otherprocedure dependent on the competence of the specialist in chemicalsynthesis. For the chemical preparation of the products of theinvention, the person skilled in the art is considered as having at hisdisposition, among other things, all the contents of “ChemicalAbstracts” and documents which are cited there.

[0050] Preferably, in the compound of formula (II) Y═Cl, R₁₄═H and n=1,that is to say

[0051]1-[(6-chloro-3-pyridinyl)methyl]-4,5-dihydro-N-nitro-1H-imidazol-2-amineor imidaclopride.

[0052] The compounds of the formula (II) can be prepared by thecorresponding procedures described, for example, in EP-A-0 192 060.

[0053] Monthly periodicity is ideally understood as meaning onetreatment every month but it is understood that the invention can bepractised at a higher rate, for example twice weekly or every threeweeks, or optionally, but in a non-preferred fashion, a slightly lowerrate, for example every five weeks.

[0054] The preferred periodicity is the monthly periodicity, a higherrate resulting in a needless consumption. In addition, the monthly ratehas the advantage of allowing the user to memorize and to plan theapplications.

[0055] When the premises contain several animals, it is preferable, andmore simple, to treat all the animals at the same time.

[0056] The efficaciously parasiticidal quantity, in the sense of theinvention, is the quantity used to eradicate fleas on the animal itselfand may thus correspond to doses already recommended for the topicaltreatment of the animal for the formulations already used commercially.Such a dose must be able to protect the animal itself for a period of atleast one month.

[0057] The dose of active compound is, preferably, between 0.3 and 60mg, and preferably between 5 and 15 mg per kilo of body weight pertreated animal.

[0058] The treatment according to the invention can be carried outcontinuously, optionally taking account of the infestation seasons whereinfestation is seasonal. Such a continuous treatment is preferred forthe premises where numerous animal entries occur, for example farms,kennels, catteries or veterinary clinics.

[0059] In a particularly preferred manner, concentrated preparations forpoint application of “spot on” type, formulae for which the preparationvolume applied to the animal is of the order of 0.3 to 1 ml, preferably0.5 ml for cats, and of the order of 0.3 to 3 ml for dogs, as a functionof the weight of the animal will be preferred.

[0060] This preparation can contain, apart from the active principleitself, a crystallization inhibitor, an organic solvent and an organiccosolvent.

[0061] Preferably, the active compound, especially the compound offormula I, can be present in the formulation at the rate of aconcentration of 1 to 20% and preferably of 5 to 15% (percentage inweight by volume).

[0062] The object of the procedure according to the invention can benon-therapeutic, involving on the one hand cleaning the hair and theskin of the animals by eliminating the parasites present and by avoidingtheir waste and excrement so that the animal has a coat which ispleasant to the eye and to the touch, likewise consisting of suppressingthe appearance and the development of fleas in the premises inhabited bythe animal.

[0063] The object can also be therapeutic when it consists in treating aparasitosis having pathogenic consequences.

[0064] The concentrated compositions for point application canadvantageously comprise:

[0065] a) the compound of formula I

[0066] b) a crystallization inhibitor, especially present at a rate of 1to 20% (W/V), preferably of 5 to 15%, this inhibitor responding to thetest according to which:

[0067] 0.3 ml of a solution comprising 10% (W/V) of the compound offormula (I) in the solvent defined under c) below, as well as 10% ofthis inhibitor, are placed on a glass slide at 20° C. for 24 hours,following which few or no crystals, especially less than 10 crystals,preferably 0 crystals, are observed with the naked eye on the glassslide,

[0068] c) an organic solvent having a dielectric constant of between 10and 35, preferably between 20 and 30, the content of this solvent c) inthe total composition preferably representing the remainder to 100% ofthe composition,

[0069] d) an organic cosolvent having a boiling point lower than 100°C., preferably lower than 80° C., and having a dielectric constant ofbetween 10 and 40, preferably between 20 and 30; this cosolvent canadvantageously be present in the composition according to aweight/weight (W/W) ratio of d)/c) of between 1/15 and 1/2. The solventis volatile in order to serve especially to promote drying and ismiscible with water and/or with the solvent c).

[0070] Although this is not preferred, the composition for pointapplication can optionally comprise water, especially at a rate of 0 to30% (volume per volume V/V), in particular of 0 to 5%.

[0071] The composition for point application can also comprise anantioxidant agent intended to inhibit oxidation in the air, this agentespecially being present at a rate of 0.005 to 1% (W/V), preferably of0.01 to 0.05%.

[0072] The compositions according to the invention intended for pets,especially dogs and cats, are applied by spotting on; this generallyconsists of a localized application on a surface zone of less than 10cm², especially of between 5 and 10 cm², in particular at two points andpreferably localized between the shoulders of the animal. Afterdeposition, the composition diffuses, especially over all the body ofthe animal, then dries without crystallizing, nor modifying theappearance especially absence of any whitish deposit or dustyappearance) nor affecting the coat.

[0073] The compositions for point application according to the inventionare particularly advantageous by virtue of their efficacy, theirrapidity of action, as well as by virtue of the pleasant appearance ofthe hair of the animals after application and drying.

[0074] As organic solvent c) which can be used in the invention, it ispossible to mention in particular: acetone, acetonitrile, benzylalcohol, butyl diglycol, dimethylacetamide, dimethylformamide,dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol,ethylene glycol monoethyl ether, ethylene glycol monomethyl ether,monomethylacetamide, dipropylene glycol monomethyl ether, liquidpolyoxyethylene glycols, propylene glycol, 2-pyrrolidone, especiallyN-methyl-pyrrolidone, diethylene glycol monoethyl ether, ethyleneglycol, diethyl phthalate, or a mixture of at least two of these.

[0075] As crystallization inhibitor b) which can be used in theinvention, it is possible to mention in particular:

[0076] polyvinilpyrrolidone, polyvinyl alcohols, copolymers of vinylacetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol,mannitol, glycerol, sorbitol, polyethoxylated sorbitan esters; lecithin,carboxymethylcellulose sodium, acrylic derivatives such as methacrylatesand others,

[0077] anionic surfactants such as alkali metal stearates, especially ofsodium, of potassium or of ammonium; calcium stearate; triethanolaminestearate; sodium abietate; alkylsulphates, especially sodiumlaurylsulphate and sodium cetylsulphate; sodiumdodecylbenzenesulphonate, sodium dioctylsulphosuccinate; fatty acids,especially those derived from copra oil,

[0078] cationic surfactants such as water-soluble quaternary ammoniumsalts of formula N⁺R′R″R′″R″″, Y⁻ in which the R radicals are optionallyhydroxylated hydrocarbon radicals, and Y⁻ is an anion of a strong acid,such as halide, sulphate and sulphonate anions; cetyltrimethylammoniumbromide is among the cationic surfactants utilizable,

[0079] the amine salts of formula N⁺R′R″R′″ in which the R radicals areoptionally hydroxylated hydrocarbon radicals; octadecylaminehydrochloride is among the cationic surfactants utilizable,

[0080] the non-ionic surfactants such as optionally polyethoxylatedsorbitan esters, in particular Polysorbate 80, polyethoxylated alkylethers; polyethylene glycol stearate, polyethoxylated castor oilderivatives, polyglycerol esters, polyethoxylated fatty alcohols,polyethoxylated fatty acids, copolymers of ethylene oxide and propyleneoxide,

[0081] amphoteric surfactants such as substituted lauryl betainecompounds, or preferably a mixture of at least two of these.

[0082] Particularly preferably, a crystallization inhibitor pair will beused, namely the combination of a surface-active agent. These agentswill especially be chosen from the compounds mentioned ascrystallization inhibitor b).

[0083] Among the filmogenic agents of particularly interesting polymerictype, it is possible to mention:

[0084] different grades of polyvinylpyrrolidone,

[0085] polyvinyl alcohols, and

[0086] copolymers of vinyl acetate and vinylpyrrolidone.

[0087] As far as surface-active agents are concerned, very particularmention will be made of non-ionic surfactants, preferablypolyethoxylated esters of sorbitan and especially the different gradesof Polysorbates, for example Polysorbate 80.

[0088] The filmogenic agent and surface-active agent will especially beable to be incorporated in close or identical quantities in the limit oftotal quantities of crystallization inhibitor otherwise mentioned.

[0089] The pair thus formed remarkably ensures the objectives of absenceof crystallization on the hair and of maintenance of the cosmeticappearance of the coat, that is to say without tendency to sticking orto sticky appearance, despite the high concentration of active material.

[0090] As cosolvent d), it is possible to mention in particular:absolute ethanol, isopropanol, methanol.

[0091] As antioxidant agent, conventional agents are especially used,such as: butylhydroxyanisole, butylhydroxytoluene, ascorbic acid, sodiummetabisulphite, propyl gallate, sodium thiosulphate, or a mixture of atleast two of these.

[0092] The compositions for point application according to the inventionare usually prepared by simple mixing of the constituents as definedabove; advantageously, a start is made by mixing the active material inthe principal solvent, and the other ingredients or adjuvants are thenadded.

[0093] In an advantageous manner, it is possible to provide forready-for-use compositions, prepared for animals of 1-10, 10-20, 20-40kg respectively.

[0094] In a particularly preferred manner, the composition according tothe invention can be present in the form of a concentrated emulsion orsolution suspension for point application on a small cutaneous zone ofthe animal, generally between the two shoulders (spot-on type solution).

[0095] The procedure according to the invention can likewise comprise,in addition, the administration of another parasiticide, preferably atthe same rate, and preferably administered concomitantly, andpreferentially with the aid of a single composition comprising a mixtureor a combination of this parasiticide and of an insecticide of formula Ior II. These combined parasiticides are not known in themselves to havean activity allowing them to act directly on the insects in the stagethereof removed from the animal, but they can be useful for furtherincreasing the efficacy against fleas resident on the animal andlikewise for reducing the possible risks of insecticide resistanceoccurring.

[0096] Among these combined parasiticides it is possible especially tomention the compounds mimicking juvenile hormones, especially:

[0097] azadirachtin—Agridyne

[0098] diofenolan (Ciba Geigy)

[0099] fenoxycarb (Ciba Geigy)

[0100] hydroprene (Sandoz)

[0101] kinoprene (Sandoz)

[0102] methoprene (Sandoz)

[0103] pyriproxyfene (Sumitomo/Mgk)

[0104] tetrahydroazadirachtin (Agridyne)

[0105] and4-chloro-2-(2-chloro-2-methylpropyl)-5-(6-iodo-3-pyridylmethoxy)pyridazine-3(2H)-oneand chitin synthesis inhibitors, especially:

[0106] chlorfluazuron (Ishihara Sangyo)

[0107] cyromazine (Ciba Geigy)

[0108] diflubenzuron (Solvay Duphar)

[0109] fluazuron (Ciba Geigy)

[0110] flucycloxuron (Solvay Duphar)

[0111] flufenoxuron (Cyanamid)

[0112] hexaflumuron (Dow Elanco)

[0113] lufenuron (Ciba Geigy)

[0114] novaluron (Isagro, Italy)

[0115] tebufenozide (Rohm & Haas)

[0116] teflubenzuron (Cyanamid)

[0117] triflumuron (Bayer)

[0118] these compounds being defined by their internationalnon-proprietary name (The Pesticide Manual, 10th edition, 1994, Ed.Clive Tomlin, Great Britain).

[0119] It is possible to mention, likewise as chitin synthesisinhibitors, compounds such as1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea,1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)phenylurea,1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea.

[0120] The preferred combined compounds are methoprenes,pyriproxyphenes, hydroprene, cyromazine, lufenuron, novaluron and1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea.

[0121] It is preferred that the administration of the two types ofcompounds is concomitant and preferably simultaneous.

[0122] Preferably, the treatment is conducted so as to administer to theanimal a dose of 0.1 to 40, and especially of 1 to 20, mg/kg for thederivative of formula I or II and a dose of 0.1 to 40, especially 1 to30, mg/kg for the combined compound.

[0123] The preferred doses are from 5 to 15 mg/kg for the compound offormula I and from 0.5 to 15 mg/kg for the combined compounds.

[0124] The proportions by weight of the compound of formula I or II andof the combined compound are, preferably, between 80/20 and 20/80.

[0125] In another form of preparation, the combined parasiticide can bean endectocidal parasiticide of macrocyclic lactone type.

[0126] Preferably, this parasiticide is chosen from the group formed bythe avermectins, ivermectin, abamectin, doramectin, moxydectin, themilbemycins and the derivatives of these compounds.

[0127] The structure, the characteristics and the processes ofproduction of these compounds are well known to the person skilled inthe art and it will be possible to refer to the widely availabletechnical and commercial literature. For the avermectins, ivermectin andabamectin, it is possible to refer, for example, to the work “Ivermectinand Abamectin”, 1989 by M. H. FISCHER and H. MROZIK, William C.CAMPBELL, ed. Springer Verlag or ALBERT-SCH™NBERG et al. (1981)“Avermectin Structure Determination”. J. Am. Chem. Soc. 103: 4216-4221.For doramectin, it will be possible to consult, especially, “VeterinaryParasitology” vol. 49 No. 1, July 1993: 5-15. For the milbemycins itwill be possible to refer, inter alia, to DAVIES H. G. et al., 1986,“Avermectins and Milbemycins”. Nat. Prod. Rep. 3: 87-121, Mrozik H. etal., 1983, Synthesis of milbemycins from avermectins, Tetrahedron lett.24: 5333-5336 as well as U.S. Pat. No. 4,134,973.

[0128] The administration of the two types of compounds can beconcomitant and preferably simultaneous in the form of a singlecomposition.

[0129] The efficacious quantity of endectocidal compound is preferablyfrom between 0.1 μg, preferentially 1 μg, and 1 mg, and in aparticularly preferred manner 5 to 200 μg/kg of animal weight. Theproportions by weight between the compound of formula (I) or (II) andthe endectocidal compound are preferably between 5/1 and 10,000/1.

[0130] The mechanisms by which the fleas disappear from the premisesthemselves are not well known and the efficacy of the invention isparticularly surprising.

[0131] An object of the present invention is likewise packed outfits orkits comprising one or more units of compositions which can be used inthe invention representing a plurality of monthly doses intended to besuccessively administered to an animal for carrying out the procedurefor a long period, for example, according to the country, for a periodof one year or for a period of one season of flea infestation.

[0132] Preferably, this kit contains a plurality of different monthlyunit doses, for example 3 or 6 (for one season) or 12 (for one year)different doses contained in as many containers of spot on or pour ontype. In this form of implementation, several kit versions are providedas a function of the weight of the animals.

[0133] The kit likewise comprises means of explanation such as a notefor ensuring the periodicity of the use of the doses.

[0134] In another form of implementation, the different doses can becontained in a single container equipped with means for ensuring theapplication of a dose corresponding to the quantity intended to beadministered monthly. This means can be, for example, a metering pump orvalve ensuring the delivery of a precise dose. It can also, more simply,be formed of a graduation with regard to a transparent containersurface, allowing the liquid volume of composition which remains in thecontainer to be known.

[0135] An object of the invention is likewise the use of a compound offormula I or of formula II for the preparation of a composition for theeradication of fleas in domestic or accommodation premises of mammals ofsmall size, especially cats and dogs, by periodic application to theanimal or the animals of the premises considered of a topicalpreparation as defined hereinabove in an efficaciously parasiticidalquantity of a compound of formula I, or optionally of formula II,according to a monthly periodicity.

[0136] Other advantages and characteristics of the invention will becomeapparent from reading the following description, by way of non-limitingexample.

EXAMPLE 1

[0137] The test used dogs in good health.

[0138] The dogs were divided by groups of three dogs into enclosures ofarea approximately 4.80 m long (16 feet) and 1.5 m wide (5 feet) eachcontaining a shelter and soil especially favourable to the developmentof the immature stages of the fleas (Ctenocephalides felis). All thedogs were voluntarily and identically preinfested and then regularlyinfested by fleas at a rate such that the total number of fleas carriedby each animal of the control group A did not fall significantly below20.

[0139] A total of 18 dogs, that is to say six enclosures, was allocatedto the control group A.

[0140] A group C of six dogs (2 enclosures) preinfested in this wayreceived the treatment according to the invention by application of acutaneous point solution having a concentration of 10% of fipronil.

[0141] The doses of concentrated composition for local cutaneousapplication of fipronil were as follows: Weight of the animal Doses 5-10 kg 0.67 ml 10-20 kg 1.34 ml 20-40 kg 2.68 ml

[0142] The animals of group C were treated on day 0 and then every 28days, that is to say the days 28, 56 and 84.

[0143] The checks (weekly counting of the eggs, counting on the body inweeks 1, 3, 5, 7, 9 and counting on the comb in weeks 2, 4, 6, 8, 10,11, 12) showed a rate of control of the infestation equal to 100%.

[0144] A similar test on cats gave the same results, that is to say atotal absence of reinfestation.

1. A method for the eradication of fleas in domestic or accommodationpremises of mammals of small size, especially cats and dogs, by periodicapplication to the animal or the animals of the premises considered of aconcentrated topical preparation for point application in anefficaciously parasiticidal quantity of a compound of formula I, oroptionally of formula II, according to a monthly periodicity. Formula I:

in which: R₁ is CN or methyl or a halogen atom; R₂ is S(O)_(n)R₃ or4,5-dicyanoimidazol-2-yl or haloalkyl; R₃ is alkyl or haloalkyl; R₄ is ahydrogen or halogen atom; or an NR₅R₆, S(O)_(m)R₇, C(O)—R₇, C(O)O—R₇,alkyl, haloalkyl or OR₈ radical or an —N═C(R₉) (R₁₀) radical; R₅ and R₆independently are the hydrogen atom or an alkyl, haloalkyl, C(O)alkyl,alkoxycarbonyl or S(O)_(r)CF₃ radical; or R₅ and R₆ can together form adivalent alkylene radical which can be interrupted by one or twodivalent heteroatoms, such as oxygen or sulphur; R₇ is an alkyl orhaloalkyl radical; R₈ is an alkyl or haloalkyl radical or a hydrogenatom; R₉ is an alkyl radical or a hydrogen atom; R₁₀ is a phenyl orheteroalkyl group which is optionally substituted by one or more halogenatoms or groups such as OH, —O-alkyl, —S-alkyl, cyano or alkyl; R₁₁ andR₁₂ are, independently of one another, a hydrogen or halogen atom, oroptionally CN or NO₂; R₁₃ is a halogen atom or a haloalkyl, haloalkoxy,S(O)_(q)CF₃ or SF₅ group; m, n, q and r are, independently of oneanother, an integer equal to 0, 1 or 2; X is a trivalent nitrogen atomor a C—R₁₂ radical, the three other valencies of the carbon atom beingpart of the aromatic ring; with the reservation that when R₁ is methyl,R₃ is haloalkyl, R₄ is NH₂, R₁₁ is Cl, R₁₃ is CF₃ and X is N; or when R₂is 4,8-dicyanoimidazol-2-yl, R₄ is Cl, R₁₁ is Cl, R₁₃ is CF₃ and X is═C—Cl. Formula II:

where Y is hydrogen or halogen R₁₄ is hydrogen or methyl and Z is—(CH₂)_(n)— with n=1 or
 2. 2. Method according to claim 1, in which inthe formula I R₁ is CN or methyl; R₂ is S(O)_(n)R₃; R₃ is haloalkyl orethyl R₄ is a hydrogen or halogen atom; or an NR₅R₆, S(O)_(m)R₇, C(O)R₇,alkyl, haloalkyl or OR₈ radical or an —N═C(R₉) (R₁₀) radical; R₅ and R₆independently are the hydrogen atom or an alkyl, haloalkyl, C(O)alkyl,S(O)_(r)CF₃ radical; or R₅ and R₆ can together form a divalent alkyleneradical which can be interrupted by one or two divalent heteroatoms,such as oxygen or sulphur; R₁₁ and R₁₂ are, independently of oneanother, a hydrogen or halogen atom; with the reservation that when R₁is methyl, R₃ is haloalkyl, R₄ is NH₂, R₁₁ is Cl, R₁₃ is CF₃ and X is N.3. Method according to claim 2 in which R₁ is CN.
 4. Method according toclaim 1 in which R₁₃ is haloalkyl, preferably CF₃.
 5. Method accordingto claim 1 in which R₂ is S(O)_(n)R₃ with R₃ being haloalkyl.
 6. Methodaccording to claim 1 in which X═C—R₁₂, R₁₂ being a halogen atom. 7.Method according to claim 1 in which R₁ is CN, R₃ is haloalkyl, R₄ isNH₂, R₁₁ and R₁₂ are independently of one another a halogen atom, and/orR₁₃ is haloalkyl.
 8. Method according to claim 1, in which the compoundis 1-[2,6-Cl₂-4-CF₃-phenyl]-3-CN-4-[SO—CF₃]-5-NH₂-pyrazole, calledfipronil.
 9. Method according to claim 1 in which, in the compound offormula (II), Y═Cl, R₁₄=H and n=1, that is to say1-[(6-chloro-3-pyridinyl)methyl]-4,5-dihydro-N-nitro-1H-imidazole-2-amineor imidaclopride.
 10. Method according to claim 1 in which the dose ofactive compound is between 0.3 and 60 mg, especially between 5 and 15 mgper kilo of body weight per treated animal.
 11. Method according toclaim 1 for a volume of preparation applied to the animal of the orderof 0.3 to 1 ml, preferably 0.5 ml for cats, and of the order of 0.3 to 3ml for dogs, as a function of the weight of the animal.
 12. Methodaccording to claim 1, for a formulation comprising, besides the activeprinciple itself, a crystallization inhibitor, an organic solvent and anorganic cosolvent.
 13. Method according to claim 1, for the preparationof a formulation in addition comprising another parasiticide.
 14. Methodaccording to claim 13 in which this other parasiticide is chosen fromthe compounds mimicking juvenile hormones or chitin synthesisinhibitors.
 15. Method according to claim 13 in which this otherparasiticide is an endectocidal parasiticide of macrocyclic lactonetype, especially chosen from the group formed by the avermectins,ivermectin, abamectin, doramectin, moxydectin, the milbemycins and thederivatives of these compounds.
 16. Packed outfits or kits comprisingone or more units of compositions for the method according to claim 1,representing a plurality of monthly doses intended to be successivelyadministered to an animal for a long period, especially for a period ofone year or for a period of one season of flea infestation.
 17. Outfitsor kits according to claim 16, characterized in that they contain aplurality of different unit doses contained in as many containers ofspot on or pour on type.
 18. Method according to claim 1, characterizedin that, when the premises contain several animals, all the animals aretreated at the same time.
 19. Method according to claim 18,characterized in that the treatment is carried out continuously,optionally taking account of the infestation seasons where infestationis seasonal.
 20. Method according to claim 18, characterized in that acomposition prepared according to claim 8 is used.